Methyl piperidine derivatives of cinnamic acids, benzoic acids, benzoazols and benzophenones useful as skin anti-aging compounds

ABSTRACT

Free radical deactivating 4- or 1,4-substituted, 2,2,6,6-tetramethyl piperidines are condensed with UV absorbing cinnamic acids or benzoic acids or benzoazols or benzophenones to produce skin anti-aging compounds and compositions which have both free radical deactivation and UV absorbing properties.

The present invention relates to compounds of general formula (I)

    (U).sub.n A                                                (I)

in which A is a group of formulae (II)-(V) ##STR1## in which R ishydrogen, C₁ -C₁₂ alkyl, C₂ -C₄ hydroxyalkyl or a polyoxyethyleneresidue containing from 2 to 20 oxyethylene units, X is oxygen or >NR₂,in which R₂ is hydrogen, a C₁ -C₁₂ alkyl or C₅ -C₈ cycloalkyl group, R₁is hydrogen, methyl or ethyl, Y is C₂ -C₆ alkylene, a diacyl residuederiving from carbonic acid or from a dicarboxylic organic acid or adicarbamoyl residue deriving from a diisocyanate, n can be the integer 1or 2, U is a group of formulae (VI)-(IX) ##STR2## in which R₃ ishydrogen or the --CN group; to a process for the preparation thereof; tothe use thereof in the preparation of compositions useful in cosmeticsand dermatology; and to the dermatological compositions containing them.

It is now believed that the cause of the major part of the alterationswhich lead to ageing of the skin are to be attributed to the action ofendogenic and exogenic free radicals. On this point, dermatology has inrecent years increasingly concerned itself with the processes and causeswhich lead to the formation of these highly reactive chemical groups,with their toxic effects and with possible defence mechanisms.

Apart from some chemical agents such as pharmaceuticals, it isprincipally physical factors, such as heat, light, UV radiation,supersonic waves and ionising radiation, which lead to the formation offree radicals.

Owing to their high reactivity, free radicals are capable of reactingeasily with other neighboring molecules, to generate further freeradicals; a chain reaction thus takes place which continues to generateradicals until it is interrupted by combination with a chemical groupwhich effects the formation of a stable molecule.

This mechanism explains the destructive action of free radicals: infact, they can bind to the elements of the cell, such as the nucleus,the proteins and particularly the membrane; consequently, alterationswhich disturb the normal metabolism appear in the cells.

The adverse action of free radicals on the skin tissue consists in anattack on the cell membranes, which causes a degradation of the fibersin the connective tissue, such as collagen and elastin, which areresponsible for the "tautness" and softness of young skin; theconsequence is ageing of the skin, which manifests itself in theappearance of dryness, scaling and wrinkles.

In nature, there are scavengers or deactivators of free radicals; theseare enzymes present in skin tissue, such as superoxide dismutase orcatalase.

These are not always sufficient for total blocking of the free radicalspresent, which can then exert their devastating action on the skintissue, which thus ages, losing its smooth and soft appearance.

A principal cause of the damage induced by free radicals appears to bethe UV fraction of solar radiation, so that the first line of defenceconsists in finding protection against the noxious action of UVradiation.

For this purpose, particular compounds have proved effective, such asso-called sunscreens which are capable of absorbing in the UV region ofsunlight, inhibiting or at least slowing down the damaging actionthereof and consequently the ageing of the skin. Numerous substanceshave been studied and used in experiments as UV absorbers, and there isextensive patent literature in existence on this topic, whereincompounds belonging to different chemical classes and capable ofabsorbing radiation from 280 to 400 nm to a greater or lesser degree areproposed. Of these compounds, however, only relatively few have beendemonstrated as being suitable for use in practice; these include theesters of p-methoxycinnamic acid and p-aminobenzoic acid, benzotriazolesand hydroxybenzophenones.

These compounds are used as sunscreens, mainly for the preparation ofcosmetic formulations which are generally used on the beach or at highaltitudes for protection from solar radiation.

Of course, sunscreens do not succeed in totally blocking the formationof free radicals, also because these can be caused by other factors, ashas already been mentioned.

A second line of defence consists therefore in cancelling out theeffects of UV radiation, that is to say in destroying or deactivatingthe free radicals which they have formed.

Again, a few substances have been proposed for this purpose as freeradical deactivators, such as, for example, vitamin E,6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, 13-cis-retinoicacid and 6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline. However, thesehave not proved to be very effective; the search for a satisfatcory andreally effective solution against solar radiation and the damagingeffects caused thereby, and hence against skin ageing, is thereforestill proceeding.

It has now been found that the compounds of the formula (I) have asurprising skin-protecting activity. In fact, such compounds are builtup by condensation of a molecule of the general formula (A) having afree-radical deactivation activity and of a molecule of the generalformula (U), capable of absorbing the radiation in the UV region of thespectrum of light.

The skin-protecting activity on the part of the compounds of the formula(I) is affected by means of two combined mechanisms of filtration of UVradiation, thereby inhibiting the generation of free radicals by thelatter at the skin level, and deactivation of the free radicals whichmay have been generated by UV radiation which has not been totallyfiltered out, or by other endogenic or exogenic factors. This propertyhas shown itself to be surprisingly superior to that to be expected fromsimple additivity of the known activities.

Therefore the present invention relates to the compounds of formula (I).Some of said compounds contain one or more chiral carbon atoms,therefore the invention also relates to the enantiomers anddiastereoisomers of compounds (I) and to the mixtures thereof. Due tothe presence of basic groups in compounds (I), the invention alsorelates to the addition salts of compounds (I) with both inorganic andorganic acids, such as hydrohalogenic, sulfuric, formic, acetic, benzoicacids.

Compounds of formula (I) are prepared by reaction of thetetramethylpiperidine derivatives of formulae (X)-(XIII) ##STR3## andthe compounds of formula R₄ --COZ, wherein R₄ CO-- represents the groupsof formulae (VI)-(IX) and Z is OH, Cl, OCH₃ or OC₂ H₅.

The condensation reaction can be carried out with methods known to thoseskilled in the art; the use of a solvent (organic or aqueous or amixture thereof) as the reaction medium is uncritical, as far as it doesnot affect the progress of the reaction. Preferably the reaction iscarried out in the absence of solvent. Catalysts promoting the reaction,such as tetrabutyl ortotitanate, can also be used.

Thanks to the advantageous characteristics of protecting action on theskin against the damages caused by UV radiations and free radicals, thecompounds of the present invention can be used in the preparation ofcompositions for the dermatological use.

According to a preferred embodiment of the invention, the abovecompositions are used for the cosmetic treatment of the skin, and theycan be in form of lotions, ointments, creams, emulsions, gels, oils,which are used as moisturizing, tonifying, detergent agents andparticularly formulations protecting against solar radiation.

Preferably, these preparations are emulsions of the oil-in-water kind,and they can contain preservatives, emulsifiers, thickening agents,antioxidants, emollients, solvents, perfumes, dyes or other substancesgenerally used in cosmetic compositions.

Generally the compositions, according to the present invention, cancontain from 0.05 up to 10% and preferably from 0.1 to 5% of thecompounds of formula I.

Of course the compounds of formula I can be added to the cosmeticcompositions also together with other sunscreens and/or free radicaldeactivators.

The following examples illustrate the invention. Examples 1-10 relate tothe preparation of compounds of formula (I), examples 11-14 concern thepreparation of cosmetic compositions containing one compound of formula(I) as the active ingredient.

EXAMPLE 1

A mixture of 18 g of methyl p-dimethylaminobenzoate, 15.7 g of2,2,6,6-tetramethyl-4-hydroxypiperidine and 0.2 ml tetrabutylortotitanate is heated and stirred for 6 hours at 170° C. The reactionproduct is recrystallized from petroleum ether at 100°/120° C. anddecolourized with decolourizing earth.

4-(p-dimethylamino-benzoyloxy)-2,2,6,6-tetramethylpiperidine is obtainedin form of a crystalline white substance with m.p. 137°-139° C. andspecific extinction (E:)--992 at 312 nm.

EXAMPLES 2-6

Following the same procedure of example 1, the compounds listed in table1 are prepared.

                                      TABLE 1                                     __________________________________________________________________________     ##STR4##                                                                     Ex. R   R.sub.5           P.f.  E:  nm                                        __________________________________________________________________________    2   CH.sub.3                                                                           ##STR5##         78-80 907 312                                       3   H                                                                                  ##STR6##         100-102                                                                             892 342                                       4   CH.sub.3                                                                           ##STR7##         111-113                                                                             872 343                                       5   H                                                                                  ##STR8##         70-72 830 310                                       6   CH.sub.3                                                                           ##STR9##         95-97 797 310                                       __________________________________________________________________________

EXAMPLES 7-10

Following the same procedure of example 1, the compounds listed in table2 are prepared.

                                      TABLE 2                                     __________________________________________________________________________     ##STR10##                                                                    Ex. R.sub.1                                                                           R.sub.5           P.f.  E:  nm                                        __________________________________________________________________________    7   H                                                                                  ##STR11##        204-206                                                                             1267                                                                              315                                       8   H                                                                                  ##STR12##        167-168                                                                             1021                                                                              310                                       9   H                                                                                  ##STR13##        177-179                                                                             1120                                                                              346                                       10  C.sub.2 H.sub.5                                                                    ##STR14##        119-121                                                                             1066                                                                              341                                       __________________________________________________________________________

EXAMPLE 11 Preparation of a Moisturizing Cream

A solution of 2 g of the compound of example 2 in 10 g of polyethyleneglycol 400 is prepared heating to 60° C.; the resulting solution isadded with 0.15 g of methyl paraben (methyl p-hydroxybenzoate) and 0.05g of propyl paraben. Separately, a mixture of 15 g of vaseline and 8 gof glyceryl monostearate is prepared and added to the above obtainedsolution, at 80° C. After that, the oily phase is added with 63.8 g ofwater pre-heated at 80° C., under strong stirring, so as to obtain anemulsion, keeping stirring until temperature is decreased below 30° C.

EXAMPLE 12 Preparation of a Lipophilic Gel

6 g of high-melting paraffin and 3.6 g of sorbitan tristearate (Span65®) are melted together and heated to 100° C.; the melted mixture isadded, under strong stirring, to 77.9 g of vaseline oil pre-heated to100° C., then it is quickly cooled to 50° C. to obtain a gel. This gelis added with a solution of 2.5 g of the compound of example 3 in 10 gof polyethylene glycol 400 previously prepared, mixing untilhomogeneity.

EXAMPLE 13 Preparation of a Sun Cream

A mixture of 10 g of cyclodimeticon/dimeticon copolymer (Dow CorningQ2-3225 C), 10 g of cyclometicon (Dow Corning 344), 0.5 g of polysorbate20 (Tween 20®), and 6 g of the compound of example 6 is prepared. Thismixture is added to a solution prepared previously, consisting of 0.2 gof 1,1'-methylene-bis-3-(3hydroxymethyl-2,4-dioxy-imidazolidinyl)urea,0.05 g of methyl paraben and 73.25 g of water.

EXAMPLE 14 Preparation of a Face Make-Up

A mixture is prepared, heating to 75° C. 78.5 g of water, 4.5 g ofglycerin, 0.6 g of 2-pyrrolidone-5-carboxylic acid and 0.2 g of methylparaben. This mixture is added with a second mixture, preparedpreviously, consisting of 3 g of octyl palmitate, 1 g of dimeticon, 4.5g of polysorbate 60 (Tween 60®), 0.1 g of propyl paraben, 7.5 g ofglyceryl monostearate and 0.2 g of the compound of example 7.

I claim:
 1. A compound selected from the group consistingof:4-(p-dimethylamino-benzoyloxy)-2,2,6,6-tetramethylpiperidine;4-(p-dimethylamino-benzoyloxy)-1,2,2,6,6,-pentamethylpiperidine;4-(p-methoxy-2-cyano-cinnamoyloxy)-2,2,6,6-tetramethylpiperidine;4-(p-methoxy-2-cyano-cinnamoyloxy)-1,2,2,6,6-pentamethylpiperidine;4-(p-methoxycinnamoyloxy)-2,2,6,6-tetramethylpiperidine;4-(p-methoxycinnamoyloxy)-1,2,2,6,6-pentamethylpiperidine;N-[2-(p-dimathylaminobenzoyloxy)ethyl]-4-(p-dimethylaminobenzoyloxy)-2,2,6,6-tetramethylpiperidine;N-[2-(p-methoxycinnamoyloxy)ethyl]-4-(p-methoxycinnamoyloxy)-2,2,6,6-tetramethylpiperidine;N-[2-(p-methoxy-2-cyano-cinnamoyloxy)ethyl]-4-(p-methoxy-2-cyano-cinnamoyloxy)-2,2,6,6-tetramethylpiperidine;andN-[2-(p-methoxy-2-cyano-cinnamoyloxy)butyl]-4-(p-methoxy-2-cyano-cinnamoyloxy)-2,2,6,6-tetramethylpiperidine.2. A composition for use in stabilizing polymers comprising at least oneof the compounds according to claim 1.